X-ray contrast media are indispensable auxiliary agents in the diagnosis of numerous diseases, such as, for example, arteriosclerotic vascular processes, tumors, infarcts, diseases of the kidneys and efferent urinary passages. Since the introduction of the first products, great advances have been made.
The chemotoxic properties of the X-ray contrast media have been greatly reduced. For clinical use this means less occurrence of side effects such as nausea, vomiting, certain circulatory reactions, urticaria, bronchial spasm and other symptoms up to shock and death. Chemotoxic effects, e.g., as LD.sub.50, are pharmacologically measurable after intravenous injection.
The products used were very strongly hypertonic (e.g., up to 8 times the osmolality of blood) and consequently caused a great number of potentially serious side effects, such as, e.g., drop in blood pressure, bradycardia to cardiac arrest, disturbances of the blood-brain barrier, intense pain, etc. Newer contrast media, used in clinically customary concentrations, exhibit only 2 to 3 times the osmolality of the blood.
Although both the chemotoxicity and the hypertonicity of the contrast media were lowered, so far no ideal values could be achieved.
Even the latest so-called nonionic contrast media still caused serious and very serious incidents (McClennan, Radiology 162, 1:1-8 [1987]: "Low-osmolality contrast media: Premises and Promises"), which have to be ascribed to chemical-toxic actions.
Also the osmolality of these products is still much too high to be able to speak of physiological contrast media. Therefore it is not surprising that at least a certain percent of patients complain about the intense pain during the examination with these products. ("Pain and hemodynamic effects in aortofemora angiography" in Acta Radiol. Diagnosis 23, 4:289-399 [1982]).
From experience these problems can be solved to a large extent by synthesis of water-soluble, very hydrophilic "nonionic dimers," i.e., of contrast media molecules, which consist of the linkage of 2 triiodinated aromatic substances. Such substances were first described in DOS 26 28 517. Since then a series of very similar structures has been described, e.g., in DOS 28 05 928, EP 0023992, EP 0049745 and EP 0108638.
Nonionic dimers are generally not hypertonic in comparison with the body fluids in all the concentrations customary for X-ray diagnosis. Further, some representatives of this substance class exhibit a very slight chemotoxicity, i.e., extremely high LD.sub.50 values are achieved after intravenous injection.
Despite these advantages, contrast media with a base of nonionic dimers thus far have hardly had any clinical use. The reason for this is the viscosity, especially of highly concentrated solutions, which are necessary for certain especially critical angiographic examinations. Thus, angiographic examinations of the coronary vessels and ventricles are to be selectively performed only with contrast media solutions which contain 350 mg of more of iodine/ml.
In this case the contrast media solutions must be injected with very high speed through about 100-cm long very narrow catheters. Solutions with over 12 to 15 cp at 37.degree. C. are hardly any longer suitable for the purpose. But also for very fast intravenous injection, as is necessary for various modern x-ray techniques, very well tolerated and slightly viscous contrast media are necessary.
The viscosity of the nonionic dimer contrast media depends on a series of factors, of which the iodine content of the molecules plays an essential role. With an increasing iodine content the viscosity of the solutions of the respective molecules decreases, but at the same time so does their solubility in water.
It is desirable to make available in high concentrations very well tolerated and water-soluble blood isotonic and at the same time slightly viscous contrast media with high iodine content.